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{{Short description|Opioid analgesic drug}} |
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{{about|the opioid drug|the stimulant α-PPP analogue|4'-Methyl-α-pyrrolidinopropiophenone}} |
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{{Redirect|MPPP}} |
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{{Hatnote|Not to be confused with ] (stimulant designer drug), ] (neurotoxic impurity of desmethylprodine synthesis) or ] (neurotoxic metabolite of MPTP).}} |
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{{drugbox | verifiedrevid = 411132219 |
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{{Infobox drug | verifiedrevid = 411133087 |
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| IUPAC_name = (1-methyl-4-phenylpiperidin-4-yl) propanoate |
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| IUPAC_name = (1-Methyl-4-phenylpiperidin-4-yl) propanoate |
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| image = MPPP.svg |
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| image = Desmethylprodine.svg |
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| alt = Skeletal formula |
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| width = 200px |
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| width = 190px |
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| image2 = Desmethylprodine molecule ball.png |
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| alt2 = Ball-and-stick model of desmethylprodine |
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<!--Clinical data--> |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category = |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_BR = F1 |
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| legal_CA = <!-- Schedule I --> |
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| legal_UK = <!-- Class A --> |
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| legal_US = Schedule I |
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| legal_DE = Anlage I |
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| routes_of_administration = |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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<!--Identifiers--> |
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| CAS_number = 13147-09-6 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 07SGC963IR |
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| ATC_prefix = |
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| ATC_suffix = |
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| PubChem = 61583 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB01478 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = C22797 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 55493 |
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| ChemSpiderID = 55493 |
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| InChI = 1/C15H21NO2/c1-3-14(17)18-15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3 |
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| InChIKey = BCQMRZRAWHNSBF-UHFFFAOYAP |
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| smiles = O=C(OC2(c1ccccc1)CCN(C)CC2)CC |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 279865 |
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| ChEMBL = 279865 |
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<!--Chemical data--> |
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| C=15 | H=21 | N=1 | O=2 |
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| smiles = O=C(CC)OC1(CCN(CC1)C)C2=CC=CC=C2 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C15H21NO2/c1-3-14(17)18-15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3 |
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| StdInChI = 1S/C15H21NO2/c1-3-14(17)18-15(9-11-16(2)12-10-15)13-7-5-4-6-8-13/h4-8H,3,9-12H2,1-2H3 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = BCQMRZRAWHNSBF-UHFFFAOYSA-N |
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| StdInChIKey = BCQMRZRAWHNSBF-UHFFFAOYSA-N |
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| synonyms = 4-propionyloxy-4-phenyl-N-methylpiperidine, MPPP, 3-desmethylprodine |
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| CAS_number = 13147-09-6 |
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| synonyms = 4-propionyloxy-4-phenyl-N-methylpiperidine, MPPP, 3-desmethylprodine |
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| ATC_prefix = |
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| ATC_suffix = |
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| PubChem = 61583 |
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| DrugBank = DB01478 |
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| C = 15 | H = 21 | N = 1 | O = 2 |
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| molecular_weight = 247.33 g/mol |
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| bioavailability = |
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| protein_bound = |
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| metabolism = |
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| elimination_half-life = |
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| excretion = |
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
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| pregnancy_US = <!-- A / B / C / D / X --> |
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| pregnancy_category= |
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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> |
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| legal_CA = <!-- Schedule I --> |
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| legal_UK = <!-- Class A --> |
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| legal_US = Schedule I |
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| legal_status = |
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| routes_of_administration = |
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}} |
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}} |
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'''MPPP''' ('''1-methyl-4-phenyl-4-propionoxypiperidine''', '''Desmethylprodine''') is an ] ] drug. It is not used in clinical practice, but has been illegally manufactured for ]. It is an ] of ] (Demerol), but since it is not used in medicine, the ] has labeled it a ] drug in the ]. In fact, it is the reversed ] of ] and is listed as having 70% of the potency of ]. |
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'''Desmethylprodine''' or '''1-methyl-4-phenyl-4-propionoxypiperidine''' ('''MPPP, Ro 2-0718''') is an ] ] drug developed in the 1940s by researchers at ].<ref>{{cite patent |country=US |number=2765314 |title=Preparation of Esters |inventor=Schmidle CJ, Mansfield RC |assign1=Rohm and Haas |gdate=2 October 1956}}</ref> '''Desmethylprodine''' has been labeled by the ] as a ] drug in the United States. It is an ] of ] (meperidine) a ] drug. Chemically, it is a reversed ] of pethidine which has about 70% of the potency of ]. Unlike its derivative ], it does not exhibit optical isomerism.<ref name="Randall, Morphine 1957 pp 310">{{cite book |vauthors=Reynolds AK, Randall LO |title=Morphine & Allied Drugs |date=1957 |page=310}}</ref> It was reported to have 30 times the activity of pethidine and a greater analgesic effect than morphine in rats, and it was demonstrated to cause central nervous system stimulation in mice.<ref name="Randall, Morphine 1957 pp 310"/> |
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==History== |
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The drug was first synthesised in 1977 for recreational purposes by a 23-year old graduate student named Barry Kidston. Kidston had apparently studied a 1947 paper by Albert Ziering.<ref>{{Cite pmid|18919744}}</ref> By reversing the ester of the meperidine skeleton, a drug approaching the potency of morphine was produced. However, the intermediate ] is liable to dehydration in acidic conditions if the reaction temperature rises above -30°C, and since Kidston did not realize this and esterified the intermediate with ] at room temperature, ] was formed as a major impurity.<ref>{{Cite pmid|6148225}}</ref> Several days after trying this new batch of his homemade drug, Kidson developed serious ] symptoms.<ref>Gibb, Barry J. (2007). ''The Rough Guide to the Brain'', Rough Guides Ltd., London, pg.166</ref> |
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Desmethylprodine was first synthesized in 1947 at Hoffman-LaRoche Laboratories by Albert Ziering and John Lee. They found that it produced effects similar to ] when administered to rats.<ref>{{cite journal |vauthors=Ziering A, Lee J |title=Piperidine derivatives; 1,3-dialkyl-4-aryl-4-acyloxypiperidines |journal=The Journal of Organic Chemistry |volume=12 |issue=6 |pages=911–4 |date=November 1947 |pmid=18919744 |doi=10.1021/jo01170a024}}</ref> Ziering had been searching for synthetic painkillers that were less addictive than morphine. The new drug was a slight variant of pethidine. It was found to be no more effective than pethidine and was never marketed.<ref name=Schwarcz>{{cite journal |title=Aim high: synthetic opiates deliver surprising side effects |vauthors=Schwarcz J |journal=Canadian Chemical News |year=2005 |volume=57 |issue=10 |pages=10 |url=https://www.thefreelibrary.com/Aim+high%3a+synthetic+opiates+deliver+surprising+side+effects.-a0151434502}}</ref> This research produced the analgesic ] (Nisentil, Prisilidine), a very closely related compound.<ref name="Randall, Morphine 1957 pp 310"/> |
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In the United States, MPPP is now in Schedule I of the ] with a zero aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.87 for the hydrochloride.<ref>{{cite web |title=Quotas - 2014 |work=DEA Diversion Control Division |url=http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |access-date=2016-02-26 |url-status=dead |archive-url=https://web.archive.org/web/20160304053357/http://www.deadiversion.usdoj.gov/fed_regs/quotas/2014/fr0825.htm |archive-date=2016-03-04}}</ref> It is listed under the ] and is controlled in most countries in the same fashion as is morphine. |
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1-methyl-4-phenylpyridinium (]), a metabolite of MPTP, causes rapid onset of irreversible symptoms similar to ].<ref>{{Cite pmid|298352}}</ref><ref name="urlSurprising Clue to Parkinsons - TIME">{{cite news |url=http://www.time.com/time/magazine/article/0,9171,1101850408-141542,00.html |title=Surprising Clue to Parkinson's - TIME |work= Time|accessdate= 2010-05-13| date=2001-06-24 | first=Claudia | last=Wallis}}</ref> ] is metabolized to the neurotoxin MPP+ by the enzyme ], which is expressed in neurons. This selectively kills brain tissue in the area of the brain called the ] and causes Parkinsonian symptoms.<ref>{{Cite pmid|11768626}}</ref> |
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== References == |
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==Toxic impurity== |
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In 1976, a 23-year-old graduate student in chemistry named Barry Kidston was searching for a way to make a ]. Having read the paper by Ziering and Lee, he deduced that he could make a drug with pethidine's effects without its legal restrictions, because desmethylprodine is a different molecule and had never been addressed by law. Kidston successfully synthesized and used desmethylprodine for several months, after which he suddenly came down with the symptoms of ] and was hospitalized. Physicians were perplexed, because Parkinson's disease would be a great rarity in someone so young, but ], the standard drug for Parkinson's, relieved his symptoms. L-DOPA is a precursor for dopamine, the neurotransmitter whose lack produces Parkinson's symptoms. |
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<references /> |
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It was later found that his development of Parkinson's was due to a common impurity in the synthesis of MPPP called ], a ] that specifically targets dopamine-producing neurons.<ref name=Schwarcz/><ref name=Gibb>{{cite book |vauthors=Gibb BJ |title=The Rough Guide to the Brain |date=2007 |publisher=Rough Guides Ltd. |location=London |page=166 |isbn=978-1-4093-5993-7 |url=https://books.google.com/books?id=sUuAuwSD2AYC&q=barry%20gibbs%20rough%20guide%20to%20the%20brain&pg=PT278}}</ref> The intermediate ] is liable to dehydration in acidic conditions if the reaction temperature rises above 30 °C. Kidston did not realize this and esterified the intermediate with ] at an elevated temperature. Consequently, he produced ] as a major impurity.<ref>{{cite journal |vauthors=Johannessen JN, Markey SP |title=Assessment of the opiate properties of two constituents of a toxic illicit drug mixture |journal=Drug and Alcohol Dependence |volume=13 |issue=4 |pages=367–74 |date=July 1984 |pmid=6148225 |doi=10.1016/0376-8716(84)90004-8}}</ref> |
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] (MPP<sup>+</sup>), a metabolite of MPTP, causes rapid onset of irreversible symptoms similar to Parkinson's disease.<ref>{{cite journal |vauthors=Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ |title=Chronic Parkinsonism secondary to intravenous injection of meperidine analogues |journal=Psychiatry Research |volume=1 |issue=3 |pages=249–54 |date=December 1979 |pmid=298352 |doi=10.1016/0165-1781(79)90006-4 |s2cid=44304872}}</ref><ref name="Surprising Clue to Parkinsons">{{cite magazine |title=Surprising Clue to Parkinson's |magazine=] |date=1985-04-08 |vauthors=Wallis C |url=https://time.com/archive/6710365/medicine-surprising-clue-to-parkinsons/ |access-date=2024-11-22 |url-status=live |archive-url=https://web.archive.org/web/20070211030319/http://www.time.com/time/magazine/article/0,9171,1101850408-141542,00.html |archive-date=February 11, 2007}}</ref> MPTP is metabolized to the neurotoxin MPP<sup>+</sup> by the enzyme ], which is expressed in glial cells. This selectively kills brain tissue in the area of the brain called the ] and causes permanent Parkinsonian symptoms.<ref>{{cite journal |vauthors=Schmidt N, Ferger B |title=Neurochemical findings in the MPTP model of Parkinson's disease |journal=Journal of Neural Transmission |volume=108 |issue=11 |pages=1263–82 |year=2001 |pmid=11768626 |doi=10.1007/s007020100004 |s2cid=2834254}}</ref> |
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{{analgesic-stub}} |
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==Analogs== |
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]s of desmethylprodine with different ''N''-substituents than a ] on the ] have been investigated. Several of these have significantly greater '']'' potency compared to desmethylprodine.<ref>{{cite journal |title=Strong Analgesics. The Preparation of Some 4-Acyloxy-1-aralkyl-4-phenylpiperidines |journal=Journal of the American Chemical Society |volume=80 |issue=18 |pages=4916–4918 |year=1958 |vauthors=Elpern B, Wetterau W, Carabateas P, Grumbach L |doi=10.1021/ja01551a038}}</ref><ref name=Sterling>{{cite journal |vauthors=Carabateas PM, Grumbach L |title=Strong Analgesics. Some 1-Substituted 4-Phenyl-4-Propionoxypiperidines |journal=Journal of Medicinal and Pharmaceutical Chemistry |volume=91 |issue=5 |pages=913–9 |date=September 1962 |pmid=14056434 |doi=10.1021/jm01240a003}}</ref><ref>{{cite journal |vauthors=Janssen PA, Eddy NB |title=Compounds related to pethidine-IV. New general chemical methods of increasing the analgesic activity of pethidine |journal=Journal of Medicinal and Pharmaceutical Chemistry |volume=2 |pages=31–45 |date=February 1960 |pmid=14406754 |doi=10.1021/jm50008a003}}</ref> |
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==See also== |
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* ] |
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* ] |
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==References== |
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{{Reflist|30em}} |
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==External links== |
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* PubChem |
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* - June 22, 1984 warning from the ] regarding MPTP byproduct in MPPP |
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{{Opioid receptor modulators}} |
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